ABSTRACT Atherosclerosis is the primary cause of coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. Despite effective lipid-lowering therapies and prevention programs, atherosclerosis is still the leading cause of mortality in the United States. Moreover, the prevalence of CHD in developing countries worldwide is rapidly increasing at a rate expected to overtake those of cancer and diabetes. Among prominent risk factors, hardening of arteries resulting from endothelial cell (EC) dysfunction, plays a causative role in promoting atherosclerosis initiation and progression. However, owing to the complexity of the endothelium and scarcity of proper molecular targets, it is widely recognized that hindering dysfunctional endothelium to prevent atheroma progression is a seemingly daunting question. Our long-term goal is to uncover and dissect molecular mechanisms governing endothelial dysfunction, and to aid rapid identification of a new class of potential regulators responsible. To this end, we show that epsins 1 and 2 are upregulated in atheromas in apolipoprotein E-deficient (ApoE-/-) mice fed with western diet (WD). Consequently, EC-specific epsins deficiency results in striking attenuation of atherosclerosis in WD fed ApoE-/- mice. Moreover, we observe that upregulation of epsins associates with downregulation of IP3R1 in both mouse and human atherosclerotic lesions. Interestingly, atherogenic mediators induce epsin binding to IP3R1 and IP3R1 downregulation in endothelial cells. Accordingly, IP3R1 loss augments ER stress, while epsin deficiency prevents IP3R1 loss and therefore attenuates ER stress. Despite these novel observations, whether sufficient IP3R1 is required for keeping ER stress at bay and blocking atheroma progression is unclear. Likewise, whether epsins promote atherosclerosis in part via mediating IP3R1 downregulation is unknown. Given that downregulation of ER stress sensors including XBP-1 correlates with IP3R1 stabilization, the ability of XBP-1 to potentiate ERAD and thereby mediate epsin-dependent IP3R1 degradation is unexplored. In pursuit of answers to these highly significant and original questions, we have formulated the central hypothesis that epsin promotes atherosclerosis by inducing downregulation of IP3R1, exacerbating ER stress, and causing endothelial dysfunction. To test our hypothesis, we propose to use novel atherosclerosis mouse models including inducible EC-specific IP3R1 deficient mice (EC-IP3R1iKO), inducible EC-specific epsin DKO mice (EC-iDKO) on EC- specific IP3R1 heterozygous background (EC-iDKO/EC-IP3R1het), and EC-specific XBP-1 deficient mice (EC- XBP-1KO) on ApoE null background. We are poised to determine the molecular mechanisms underlying epsins mediating IP3R1 degradation in atherosclerosis; and molecular mechanisms by which ER stress sensors potentiate epsin-mediated IP3R1 degradation. If fruitful, our findings will hold a high probability of uncovering a counter-intuitive role for endothelial IP3R1 in atherosclerosis, offering a new class of therapeutic strategies by targeting epsins, and inaugurating a paradigm shift in research to combat atherosclerosis.